Synthesis of 10,11‐Didehydro Cinchona Alkaloids and Key Derivatives

A series of 10,11‐didehydro Cinchona alkaloids containing an ethynyl group at C(3) were prepared efficiently in two steps from the naturally occurring Cinchona alkaloids (Scheme 1). 10,11‐Didehydroquinine ( 4c ) and 10,11‐didehydroquinidine ( 4a ) belong to a significantly new class of semi‐natural Cinchona alkaloids. They are more polar and basic than the natural compounds and serve as versatile building blocks for further functionalization; they were transformed into the corresponding 11‐halo and 11‐pseudohalo derivatives and (Z)‐vinyl halides (Schemes 2 and 3). The conformation of the alkaloids was elucidated by NOE and X‐ray crystal diffraction analysis of 4a (Fig.), and the cytostatic activity of selected didehydroquinidine derivatives was evaluated (Table 5).     

Antiviral properties of photosensitizers

Abstract— We have studied the antiviral properties of three different groups of photo-sensitizers, viz. (i) various furyl compounds; (ii) β-carboline alkaloids; (iii) thiophenes and their acetylene derivatives. In general the antiviral potency of the furyl compounds correlated with their ability to produce DNA photoadducts. Among the naturally occurring β-carboline alkaloids, harmine was considerably more potent (in the presence of long wavelength UV radiation, UVA) than several other harmane-related compounds. Slight alterations in chemical structure had profound effects on their antiviral activities. Harmine was shown to inactivate the DNA-virus murine cytomegalovirus (MCMV) by inhibiting viral gene expression, although other targets may also exist. Several eudistomins, carboline derivatives isolated from a tunicate, were also photoactive against viruses. Various plant thiophenes and polyacetylenes were studied in detail. These compounds also required UVA for antiviral activity, and some of them were extremely potent against viruses with membranes, e.g. α-terthienyl, which showed significant activity at only 10^-5μg/ml. When MCMV had been treated with α-terthienyl plus UVA, the virus retained its integrity and penetrated cells normally; but the virus did not replicate. More than 30 additional thiophenes have recently been evaluated, including many synthetic ones, and some of these are even more potent than a-terthienyl. We believe that certain thiophenes possess potential therapeutic value and should be tested against model virus infections in animals.     

Automated multiple development thin-layer chromatography for separation of opiate alkaloids and derivatives

There are three types of opiate alkaloids. First, the poppy alkaloids: morphine, codeine, thebaine, noscapine and papaverine; then, the semi-synthetic and synthetic derivatives used in therapy as antitussives and analgesics, such as pholcodine, ethylmorphine and dextromethorphan; at last narcotic compounds, diacetylmorphine (heroin) and opiates employed as substitutes in treatment of addiction: buprenorphine and methadone. For classical thin-layer chromatography (TLC) of opium alkaloids, it is necessary to use complex eluents with strong alkaline substances to obtain a clean separation between morphinan and isoquinoline compounds. This study purposes the planar chromatographic analysis of these substances by the automated multiple development (AMD) compared with results obtained by classical TLC method. The aim of this work was to achieve the best separation of these opiate alkaloids and derivatives by this modern technique of planar chromatography. The AMD system provided a clean separation for each of three opiates groups studied and the best results have been obtained with universal gradient: methanol 100, methanol-dichloromethane 50/50, dichloromethane 100, dichloromethane 100, hexane 100 for opium alkaloids and with gradient A: 5% of 28% ammonia in methanol 100, acetone 100, acetone 100, ethyl acetate-dichloromethane 50/50, dichloromethane 100 for antitussives and substitutes. Two reagents were used for the detection of alkaloids by spraying: Dragendorff and iodoplatinate reagents. The detection limits with these two reagents were 1 microg for ethylmorphine, thebaine, papaverine, codeine, and 2 microg for morphine and noscapine and other alkaloids.     

Mass spectral characterization of ergot alkaloids by electrospray ionization, hydrogen/deuterium exchange, and multiple stage mass spectrometry: Usefulness of precursor ion scan experiments

Six ergot alkaloids belonging to the lysergic acid derivatives (ergonovine (EGN) and methysergide hydrogen maleinate (MHM)) and peptide-type derivatives (ergocristine (EGR), ergotamine (EGT), ergocornine (EGC) and alpha-ergokryptine (EGK)) were studied by positive electrospray tandem mass spectrometry. The fragmentation mechanisms of these compounds were studied by collision-induced dissociation (CID) using triple quadrupole and ion trap mass spectrometers, and the nature of the major product ions further confirmed by hydrogen/deuterium (H/D) exchange experiments. A common abundant product ion at m/z 223 was characteristic of the two classes of ergot alkaloids. Therefore, a precursor ion scan of m/z 223 that triggers information data acquisition (IDA) in combination with CID experiments was used to identify other potential ergot alkaloids. Using this approach, it was possible to confirm the presence of ergosine, another peptide-type ergot alkaloid, in a rye flour extract at trace levels.     

Synthesis and spatial structure of 1-(cytisin-1-ylmethyl)benzimidazole-2-thione

New derivatives of cytisine and anabasine alkaloids containing benzothiazole and benzimidazole fragments were discussed. Physicochemical characteristics of the new compounds were determined. The structure of 1-(cytisin-1-yl-methyl)benzimidazole-2-thione was studied by X-ray diffraction analysis.     

Ruspolia hypercrateriformisM.R.: Isolierung und Strukturaufklärung von neuen Pyrrolidin-Alkaloiden. 169. Mitt. über organische Naturstoffe

Ruspolia hypercrateriformis M.R. : Isolation and Structure Elucidation of New Pyrrolidine Alkaloids Three new pyrrolidine alkaloids have been isolated from Ruspolia hypercrateriformis, which belongs to the plant family of Acanthaceae. The structure of the alkaloids ruspolinone ( 1 ), norruspolinone ( 2 ) and norruspoline ( 3 ) (Scheme 1) has been elucidated by means of spectroscopic data of the pure compounds and their derivatives, by chemical transformation fo 2 to 1 by methylation, by trans-formation of 3 and 2 to identical hydrogenation products, and by comparison of degradation products with synthetically prepared model compounds.     

Organic catalysis of phospha-aldol condensation

Phospha-aldol reaction of dialkylphosphites with carbonyl compounds is catalyzed by cinchonine alkaloids and thier modified derivatives to give optically active hydroxyphosphonates. The use of diastereomeric pairs of alkaloids allowed obtaining both optical antipodes of hydroxyphosphonates. Cinchonine alkaloids show the highest enantioselectivity as organic catalysts. It was found that ordinary crystallization of some enantiomerically enriched hydroxyphosphonates leads to isolation of the enantiomerically pure stereoisomers. Hydroxyphosphonic acids were obtained by hydrolysis of phosphonates. Fluoroalkylphosphonates were obtained by reaction with diethylaminotrifluorosulfurane (DAST).     

Nonaqueous capillary electrophoresis-electrospray ionization-ion trap-mass spectrometry analysis of pyrrolo- and pyrido[1,2-a]azepine alkaloids in Stemona

Stemona alkaloids represent an outstanding class of natural compounds due to their pharmacological profile and their complex and unusual molecular structures. The aim of this study was the development of the first CE method for the separation, identification and quantification of these pyrrolo- and pyrido[1,2-a]azepine derivatives in three Stemona species. The best results were obtained with a NACE-ESI-IT-MS method, utilizing an electrolyte of 50 mM ammonium acetate, 1 M acetic acid and 10% methanol in ACN and a separation voltage of 30 kV. Samples were injected voltage-assisted with 20 kV for 1 s. Isopropanol:water (1:1) was used as ESI sheath liquid at a flow rate of 3 microL/min. The assay was applied for the qualitative profiling of Stemona alkaloids in S. curtisii, S. collinsae and S. tuberosa. For unambiguous peak assignment of more than forty unidentified alkaloids MS/MS experiments were performed and fragmentation patterns studied. Subsequently the method was validated for the quantitative determination of four selected derivatives (RSD inter- and intraday <6%, LODs <7.5 microg/mL, LOQs <25.0 microg/mL, for all analytes, recovery rates >98.9%) in several Stemona sp. extracts.     

Structure activity relationship studies on antileishmanial steroidal alkaloids from Sarcococca hookeriana

The search for antileishmanial constituents from the medicinal plant Sarcococca hookeriana (Buxaceae) of Nepalese origin has resulted in the isolation of 17 (1-17) active steroidal alkaloids. Compounds 1, 2, and 10 were subjected to derivatization and five chemically derived derivatives (1a, 2a, 10a, 10b, 10c) were also obtained. All these natural compounds and derivatives were found to have potent to mild antileishmanial properties. The IC(50) values were found to be in the range of 0.20-61.44 microg mL(-1) (IC(50) value of standard drug amphotericin B = 0.12 microg mL(-1)). The structure activity relationship indicated that the varieties of functionalities present in ring A of the steroidal alkaloids were found to play a characteristic role to increase the antileishmanial activity.     

Cryptolepine Derivatives: Quadruplex-Interactive Agents as Inhibitors of Human Telomerase

Alkaloids are very important natural products. Most of them have biologic activity. Many novel drugs have been developed based on alkaloids, such as camptothecin, taxol, vinblastine. A series of novel cryptolepine derivatives were synthesized (Figure 1). The interaction of cryptolepine derivatives with G-quadruplex (Figure 2) was studied by CD and UV spectra.[1] Most of these compounds can induce the formation of G-quadruplex and stabilize the formed G-quadruplex, resulting in the inhibitory effect on telomerase. Most of these cryptolepine derivatives have potent cytotoxicity in vitro against human tumor cell line.     

Developments in the research of new antitumor agents (review)

The following review discusses major directions in the research and preparation of various classes of advanced antitumor agents: synthetic materials which work by an alkylating mechanism (derivatives of di (2-chloroethyl)amine, ethylenimine, alkylnitrosourea, dimethyltriazines); platinum derivatives; dispiropiperazines; alkylating agents derived from polyols; various antimetabolites; as well as compounds derived from natural products, such as anthracycline antibiotics, bleomycin, actinomycin, mitomycin, derivatives of aureolic acid, etc. Also discussed are the use of enzymes to destroy substances needed for tumor growth; new plant alkaloids which inhibit mitosis (Vinca alkaloids, Podophyllin toxins, colchamine, etc.); and immunomodulating agents.Dedicated to the memory of S. A. Giller, researcher and leader blessed with an unusually keen sense for new challenges.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 18–31, January, 1985.     

Synthesis and intramolecular heterocyclization of <Emphasis Type="Italic">n</Emphasis>-allylthiocarbamide derivatives of the alkaloids cytisine and anabasine into 1,3-thiazoline derivatives and features of their molecular structures

Allylthiourea derivatives were synthesized from the alkaloids cytisine and anabasine and allylisothiocyanate. 1,3-Thiazoline derivatives were synthesized from them via intramolecular heterocyclization using HCl and heating in a sealed ampul. The structures of the synthesized compounds were proved by IR and PMR spectroscopy, mass spectrometry, and x-ray structure analysis.     

Enantioselective synthesis of β-amino esters bearing a quinazoline moiety via a Mannich-type reaction catalyzed by a cinchona alkaloid derivative

The cinchona alkaloids catalyzed the direct asymmetric Mannich reactions of 1,3-dicarbonyl compounds with acyl imines to produce novel β-amino ester derivatives containing a quinazoline moiety.The adducts were isolated with high enantiomeric excess(up to 99%).     

Natural products active against African trypanosomes: a step towards new drugs

This review covers compounds with activity on African trypanosomes (mainly Trypanosoma brucei subsp.,T congolense and T vivax) isolated from natural sources and is organized according to the structure of the etabolites (alkaloids, phenolic derivatives, quinones, terpenes and other metabolites). The literature from he mid-1980s up to June 2003 is reviewed and 89 references are cited.     

A novel synthetic approach for the synthesis of pyridocarbazole alkaloids

The synthesis of 11‐methyl‐6H‐pyrido[4,3‐b]carbazole‐1(2H)‐one (5), which can be important for the synthesis of other pyridocarbazole alkaloids and especially 1‐substituted ellipticines, is described. Construction of the tetracyclic structure was achieved by a new route and two important precursor compounds (4a and 4b) for the synthesis of pyridocarbazole alkaloids and also many new tetrahydrocar‐bazole derivatives (7, 8, 9, 10, 11, 12, 13) were synthesized.     

Synthesis of chiral dihydrofuran compounds by thiourea derivatives-catalyzed“interrupted”Feist-Bénary reaction

<正>In this study,six thiourea derivatives of cinchona alkaloids with 9-nat or 9-epi-configuration were synthesized.After characterized the structures,we adopted them to the asymmetric"interrupted"Feist-Benary(IFB) reaction ofα-haloketones with β-dicarbonyl compounds,to give optically active dihydrofurans.Various thiourea derivatives as organocatalysts were examined.The corresponding chiral hydroxyl dihydrofurans have been obtained in excellent yields and moderate ees.To the acyclic substrate,we obtained exciting and promising result.     

Aconitum lipo-alkaloids--semisynthetic products of the traditional medicine

The term lipo-alkaloid is used for C19 aconitane alkaloids containing one or two long-chain fatty acid residues. Lipo-alkaloids are transesterified derivatives of the most toxic and highly effective diester-type diterpene alkaloids, such as aconitine, hypaconitine, mesaconitine. Lipo-alkaloids are native minor compounds of aconite drugs, but their amount significantly increases after traditional processing, which is a general method in the Far Eastern traditional medicinal systems. Analytical works demonstrated that cautious processing (usually boiling) of crude aconite roots decreases the amount of normal diterpene alkaloids and increases the concentration of lipo-alkaloids resulting in the reduction of toxicity of the drugs. Many papers reported that lipo-alkaloids occur as a complex mixture in the drugs, and the isolation of the individual components is extremely difficult. These compounds have been identified using highly sensitive analytical methods (HPLC-MS, NMR), and semisynthetic approaches have been developed to ensure lipo-alkaloids in pure form for pharmacological studies. This review summarizes the structure, chemistry, semisynthesis, analytics and bioactivities of lipo-alkaloids. On the basis of 32 references this is the first comprehensive study on this topic, covering the data of 173 compounds.     

The chemistry and biology of organic guanidine derivatives

Organic guanidine compounds are reviewed, with emphasis on natural products isolation, identification, synthesis and biological activities. The literature survey includes purely synthetic guanidine derivatives, guanidine alkaloids and non-ribosomal peptides from bacteria and cyanobacteria, as well as related compounds isolated from marine and terrestrial invertebrates and higher plants.     

Preparation, structure and spasmolytic activities of some derivatives of harmine series of alkaloids

Keeping in view the interesting chemistry and pharmacological importance of harmine series of bases -- the beta-carboline alkaloids, a number of new derivatives of tetrahydroharmine and harmalol have been prepared and characterized through spectral studies. Some of these derivatives showed spasmolytic activity. It was observed that all the N-acyl tetrahydroharmine derivatives are stable, not labile and no ring opening occurs in these compounds, as reported recently.     

Organocatalytic asymmetric vinylogous addition to quinones - formation of optically active alpha-aryl ketones

The first organocatalytic addition of dicyanoalkylidenes to quinones catalyzed by Cinchona alkaloids leading to formation of 1,4-diketone derivatives with high diastereomeric ratios (up to >98 : <2 dr) and enantioselectivities (up to 99% ee) has been developed; the optically active compounds obtained are useful for a number of transformations, e.g. the synthesis of optically active alpha-aryl ketones.